The present invention relates to processes for the preparation of 2,3-dihydrothiepine derivatives.
Heretofore, a process for synthesizing a 2,3-dihydrobenzothiepine derivative by subjecting phenylthiobutyric acid to an intramolecular cyclodehydration, introducing a C1 unit into the xcex1-position of the obtained ketone body, and conducting reduction and dehydration is disclosed in patent applications such as PCT/JP98/05708 (WO99/32100) and Japanese Patent Application No. 10-363404 (PCT/JP99/07148). Moreover, as a cyclization reaction of the Dieckmann type, a process proposed by Nagamatsu et al., (J. Heterocyclic Chem., 28, 513 (1991)), a process disclosed in WO098/55475, etc. are known. However, these processes use raw material difficult to get, reagents having a disposal problem or reagents not suitable for large-scale synthesis. In addition, the processes have long steps and require complicated operations.
Because of the above-mentioned present conditions, there is a demand for a process for producing a 2,3-dihydrothiepine derivative, the process being inexpensive, simple and more suitable for large-scale synthesis.
The inventors of the present invention made a variety of studies, and as a result, they have found a process for preparing a 2,3-dihydrothiepine derivative by causing a sulfide having a propyl group as a substituent, the propyl group having an xcex1,xcex2 unsaturated carbonyl group and an electron-attracting group at its end, to react with a base in a solvent. Furthermore, they found a process for preparing a 2,3-dihydrothiepine derivative by causing an orthohalogenobenzaldehyde to react with a propanethiol having an electron-attracting group at its 4-position. As a result of further studies based on these findings, they have accomplished the present invention.
Namely, the present invention relates to:
(1) a process for preparing a compound represented by the following formula: 
xe2x80x83wherein each symbol is as defined below, or a salt thereof, characterized by subjecting a compound represented by the following formula: 
xe2x80x83wherein R1 is an electron-attracting group; R2, R3, R4, R5 R6 and R7 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, provided that R6 and R7 may be united to form a ring; and R8 is a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof, to a ring-closing reaction;
(2) the preparation process according to the above-mentioned (1) wherein R1 is an esterified carboxyl group;
(3) the preparation process according to the above-mentioned (1) wherein R8 is a hydrogen atom;
(4) the preparation process according to the above-mentioned (1) wherein R2, R3, R4 and R5 are each a hydrogen atom;
(5) the preparation process according to the above-mentioned (1) wherein the reaction is conducted in the presence of a base;
(6) the preparation process according to the above-mentioned (5) wherein the base is an alcoholate;
(7) the preparation process according to the above-mentioned (1) wherein the reaction is conducted in a solvent containing a carbonic acid diester;
(8) a process for preparing a compound represented by the following formula: 
xe2x80x83wherein each symbol is as defined below, or a salt thereof, characterized by subjecting a compound represented by the following formula: 
xe2x80x83wherein R1 is an electron-attracting group; R2, R3, R4 and R5 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; ring A is an optionally substituted benzene ring; and R8 is a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof, to a ring-closing reaction;
(9) the preparation process according to the above-mentioned (8) wherein R1 is an esterified carboxyl group;
(10) the preparation process according to the above-mentioned (8) wherein R8 is a hydrogen atom;
(11) the preparation process according to the above-mentioned (8) wherein R2, R3, R4 and R5 are each a hydrogen atom;
(12) the preparation process according to the above-mentioned (8) wherein the reaction is conducted in the presence of a base;
(13) the preparation process according to the above-mentioned (12) wherein the base is an alcoholate;
(14) the preparation process according to the above-mentioned (8) wherein the reaction is conducted in a solvent containing a carbonic acid diester;
(15) a process for preparing a compound represented by the following formula: 
xe2x80x83wherein each symbol is as defined below, or a salt thereof, characterized by causing a compound represented by the following formula: 
xe2x80x83wherein X is a leaving group; and R6 and R7 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, provided that R6 and R7 may be united to form a ring; and R8 is a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof, to react with a compound represented by the following formula: 
xe2x80x83wherein R1 is an electron-attracting group; R2, R3, R4 and R5 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or a salt;
(16) the preparation process according to the above-mentioned (15) wherein X is a halogen atom;
(17) the preparation process according to the above-mentioned (15) wherein X is a fluorine atom;
(18) the preparation process according to the above-mentioned (15) wherein R1 is an esterified carboxyl group;
(19) the preparation process according to the above-mentioned (15) wherein R8 is a hydrogen atom;
(20) the preparation process according to the above-mentioned (15) wherein R2, R3, R4 and R5 are each a hydrogen atom;
(21) A process for preparing a compound represented by the following formula: 
xe2x80x83wherein each symbol is as defined below, or a salt thereof, characterized by causing a compound represented by the following formula: 
xe2x80x83wherein X is a leaving group; R8 is a hydrogen atom or an optionally substituted hydrocarbon group; and ring A is an optionally substituted benzene ring, or a salt thereof, to react with a compound represented by the following formula: 
xe2x80x83wherein R1 is an electron-attracting group; R2, R3, R4 and R5 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or a salt thereof;
(22) the preparation process according to the above-mentioned (21) wherein X is a halogen atom;
(23) the preparation process according to the above-mentioned (21) wherein X is a fluorine atom;
(24) the preparation process according to the above-mentioned (21) wherein R1 is an esterified carboxyl group;
(25) the preparation process according to the above-mentioned (21) wherein R8 is a hydrogen atom;
(26) the preparation process according to the above-mentioned (21) wherein R2, R3, R4 and R5 are each a hydrogen atom;
(27) a process for preparing a compound represented by the following formula: 
xe2x80x83wherein each symbol is as defined below, or a salt thereof, characterized by subjecting a compound represented by the following formula: 
xe2x80x83wherein R1 is an electron-attracting group; R2, R3, R4, R5, R6 and R7 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; and R9 is an optionally substituted hydrocarbon group; provided that R6 and R7 may be united to form a ring, or a salt thereof, to a ring-closing reaction in the presence of an alcoholate in a solvent containing a carbonic acid diester;
(28) the preparation process according to the above-mentioned (27) wherein R1 is an esterified carboxyl group;
(29) the preparation process according to the above-mentioned (27) wherein each of R2, R3, R4 and R5 is hydrogen;
(30) a process for preparing a compound represented by the following formula: 
xe2x80x83wherein each symbol is as defined below, or a salt thereof, characterized by subjecting a compound represented by the following formula: 
xe2x80x83wherein R1 is an electron-attracting group; R2, R3, R4 and R5 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; R9 is an optionally substituted hydrocarbon group; and ring A is an optionally substituted benzene ring, or a salt thereof, to a ring-closing reaction in the presence of an alcoholate in a solvent containing a carbonic acid diester;
(31) the preparation process according to the above-mentioned (30) wherein R1 is an esterified carboxyl group;
(32) the preparation process according to the above-mentioned (30) wherein each of R2, R3, R4 and R5 is hydrogen;
(33) a compound represented by the following general formula: 
xe2x80x83wherein R1 is an electron-attracting group; R2, R3, R4 and R5 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; ring A is an optionally substituted benzene ring; and R8 is a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof;
(34) the preparation process according to the above-mentioned (33) wherein R1 is an optionally esterified carboxyl group;
(35) the preparation process according to the above-mentioned (33) wherein R8 is a hydrogen atom;
(36) the preparation process according to the above-mentioned (33) wherein R2, R3, R4 and R5 are each a hydrogen atom;
(37) a process for preparing a compound represented by the following formula: 
xe2x80x83wherein each symbol is as defined below, or a salt thereof, characterized by causing a compound represented by the following formula: 
xe2x80x83wherein X is a leaving group; R8 is a hydrogen atom or an optionally substituted hydrocarbon group; and ring A is an optionally substituted benzene ring, or a salt thereof, to react with a compound represented by the following formula: 
xe2x80x83wherein R1 is an electron-attracting group; R2, R3, R4 and R5 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or a salt;
(38) the preparation process according to the above-mentioned (37) wherein R1 is an esterified carboxyl group;
(39) the preparation process according to the above-mentioned (37) wherein R8 is a hydrogen atom;
(40) the preparation process according to the above-mentioned (37) wherein R2, R3, R4 and R5 are each a hydrogen atom;
(41) the preparation process according to the above-mentioned (37) wherein X is a halogen atom; and
(42) the preparation process according to the above-mentioned (37) wherein X is a fluorine atom.
The xe2x80x9celectron-attracting groupxe2x80x9d used in this specification is exemplified by (i) optionally esterified or amidated carboxyl groups; (ii) groups represented by the formula: xe2x80x94(CO)R9, wherein R9 is an optionally substituted hydrocarbon group; (iii) a nitrile group; (iv) a nitro group; (v) groups represented by the formula: xe2x80x94(SOm)R10, wherein m is 1 or 2 and R10 is an optionally substituted hydrocarbon group; (vi) groups represented by the formula: xe2x80x94PR11R12, wherein R11 and R12 are each an optionally substituted hydrocarbon group; (vii) groups represented by the formula: xe2x80x94(PO)(OR13)(OR14), wherein R13 and R14 are each hydrogen or an optionally substituted hydrocarbon group; (viii) optionally substituted aryl groups; (ix) optionally substituted alkenyl groups; (x) halogen atoms (for example, fluorine, chlorine, bromine and iodine); and (xi) a nitroso group, preferably by optionally esterified or amidated carboxyl groups, groups represented by the formula: xe2x80x94(CO)R9, a nitrile group, a nitro group, groups represented by the formula: xe2x80x94(SOm)R10, groups represented by the formula: xe2x80x94PR11R12 and groups represented by the formula: xe2x80x94(PO)(OR13)(OR14), and more preferably by esterified carbonyl groups (for example, carbonyl groups esterified with C1-4 alkyl such as methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl.)
The xe2x80x9cesterified carboxyl groupsxe2x80x9d in the above-mentioned (i) xe2x80x9coptionally esterified of amidated carboxyl groupsxe2x80x9d are exemplified by groups represented by the formula: xe2x80x94(CO)OR15, wherein R15 is hydrogen or an optionally substituted hydrocarbon group and the xe2x80x9camidated carboxyl groupsxe2x80x9d are exemplified by groups represented by the formula: xe2x80x94(CO)NR16R17, wherein R16 and R17 are each hydrogen or an optionally substituted hydrocarbon group and also may be united to form a 5- to 7-membered (preferably, a 5- to 6- membered) cyclic amino together with the nitrogen atom adjoining R16 and R17, such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole.
In the above-recited formula (vi) or (vii), R11 and R12, or R13 and R14 may be united to form, for example, a lower (C2-6) alkylene (for example, dimethylene, trimethylene and tetramethylene), a lower (C2-6) alkenylene (for example, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94), and a lower (C4-6) alkadienylene (for example, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94), preferably a lower (C1-6) alkylene, more preferably a lower (C4-6) alkylene. These divalent groups may have a substituent, whose examples include a hydroxyl group, halogens, C1-4 alkyls, C1-4 alkoxys.
The xe2x80x9caryl groupsxe2x80x9d in the above-mentioned (viii) optionally substituted aryl groups are exemplified by C6-14 aryls such as phenyl and naphthyl, preferably C6-10 aryls, and more preferably phenyl. The aryl groups may have from one to three substituents such as those the below-mentioned xe2x80x9coptionally substituted hydrocarbon groupsxe2x80x9d may have.
The xe2x80x9calkenyl groupsxe2x80x9d in the above-mentioned (ix) optionally substituted alkenyl groups are exemplified by alkenyls having from two to ten carbon atoms such as vinyl, allyl, crotyl, 2-pentenyl and 3-hexenyl, preferably lower (C2-6) alkenyls, and more preferably vinyl. The alkenyl groups may have from one to three substituents such as those the below-mentioned xe2x80x9coptionally substituted hydrocarbon groups xe2x80x9d may have.
The xe2x80x9chydrocarbon groupsxe2x80x9d in the xe2x80x9coptionally substituted hydrocarbon groupsxe2x80x9d used in this specification are exemplified by
(1) alkyls (for example, C1-10 alkyls such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl, and preferably lower (C1-6) alkyls);
(2) cycloalkyls (for example, C3-7 cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl);
(3) alkenyls (for example, alkenyls having from two to ten carbon atoms such as vinyl, allyl, crotyl, 2-pentenyl and 3-hexenyl);
(4) cycloalkenyls (for example, cycloalkenyls having from three to seven carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl and 2-cyclohexenylmethyl);
(5) alkynyls (for example, alkynyl having from two to ten carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl and 3-hexynyl, and preferably lower (C2-6) alkynyls)
(6) aryls (for example, C6-14 aryls such as phenyl and naphthyl, preferably C6-10 aryls, and more preferably phenyl);
(7) aralkyls (for example, phenyl-C1-4 alkyls (example, benzyl and phenethyl)). Particularly, alkyls are preferable and C1-4 alkyls such as methyl and ethyl are more preferable. Especially, methyl is preferably used.
The hydrocarbon groups may have a substituent, examples of which include halogens (for example, fluorine, chlorine, bromine and iodine), nitro, cyano, a hydroxyl group, optionally substituted thiol groups (for example, thiol and C1-4 alkylthios), optionally substituted amino groups (for example, amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, and 5- to 6-membered cyclic aminos such as tetrahydropyrrole, piperazine, piperidine, morpholine, thio morpholine, pyrrole and imidazole), optionally esterified or amidated carboxyl groups (for example, carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyls and di-C1-4 alkylcarbamoyls), C1-4 alkyls which may be substituted with a halogen atom or a C1-4 alkoxy (for example, trifluoromethyl, methyl and ethyl), C1-4 alkoxys which may be substituted with a halogen atom or a C1-4 alkoxy (for example, methoxy, ethoxy, trifluoromethoxy and trifluoroethoxy), formyl, C2-4 alkanoyls (for example, acetyl and propionyl), C1-4 alkylsulfonyls (for example, methanesulfonyl and ethanesulfonyl), and C1-4 alkylsulfinyls (for example, methanesulfinyl and ethanesulfinyl). The number of such substituents is preferably from one to three.
Examples of the xe2x80x9chalogen atomxe2x80x9d represented by R2, R3, R4 R5, R6 and R7 in the above-recited formulas include fluorine, chlorine, bromine and iodine.
Examples of the xe2x80x9coptionally substituted amino groupsxe2x80x9d represented by R2, R3, R4, R5, R6 and R7 in the above-recited formulas include amino groups that may be substituted with the above-mentioned xe2x80x9coptionally substituted hydrocarbon groups.xe2x80x9d The number of such substituents may be any of one to two. When two substituents are present, the two substituents may be the same or different. The two substituents may be united to form 5- to 7-membered (preferably 5- to 6-membered) cyclic amino (for example, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole) together with a nitrogen atom adjoining the two substituents.
Examples of the xe2x80x9coptionally substituted hydroxyl groupsxe2x80x9d represented by R2, R3, R4, R5, R6 and R7 in the above-recited formulas include hydroxyl groups that may be substituted with the above-mentioned xe2x80x9coptionally substituted hydrocarbon groups.xe2x80x9d
Examples of the xe2x80x9coptionally substituted thiol groupsxe2x80x9d represented by R2, R3, R4, R5, R6 and R7 in the above-recited formulas include thiol groups that may be substituted with the above-mentioned xe2x80x9coptionally substituted hydrocarbon groups.xe2x80x9d
The xe2x80x9cheterocyclic groupxe2x80x9d in the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d used in this specification is exemplified by 5- to 7-membered aromatic heterocyclic rings containing from one to three kinds (preferably, from one to two kinds) of at least one (preferably, from one to four, more preferably from one to two) hetero atoms selected form an oxygen atom, a sulfur atom, a nitrogen atom and the like, and saturated or unsaturated non-aromatic heterocyclic rings (aliphatic heterocyclic rings).
Examples of the xe2x80x9caromatic heterocyclic ringsxe2x80x9d include 5- to 6-membered monocyclic heterocyclic rings (for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine). Examples of the xe2x80x9cnon-aromatic heterocyclic ringsxe2x80x9d include 5- to 7-membered (preferably, 5- to 6-membered) saturated or unsaturated (preferably, saturated) non-aromatic heterocyclic rings (aliphatic heterocyclic rings) and the like, or 5- to 6-membered non-aromatic heterocyclic rings resulting from a part or all of the double bonds of the above-mentioned aromatic monocyclic heterocyclic rings. As such heterocyclic rings, 5- to 6-membered aromatic rings are desirable, and furan, thiophene, pyrrole, pyridine (preferably, 6-membered rings) and the like are more desirable.
The substituents which the heterocyclic rings may have are exemplified by substituents such as those the above-mentioned xe2x80x9coptionally substituted hydrocarbon groups.xe2x80x9d The number of such substituents may be from one to three.
In the above-recited formulas, an esterified carboxyl group is desirable as R1, and a hydrogen atom is desirable as R8. As R2, R3, R4 and R5, a hydrogen atom or optionally substituted hydrocarbon groups are desirable and a hydrogen atom is more desirable. R6 and R7 are preferably united to form an optionally substituted benzene ring.
The substituent which the xe2x80x9coptionally substituted benzene ringxe2x80x9d used in this specification may have is exemplified by substituents such as those the above-mentioned xe2x80x9coptionally substituted hydrocarbon groupsxe2x80x9d may have; the above-mentioned xe2x80x9coptionally substituted aryl groupsxe2x80x9d which may be combined through a spacer (for example, divalent groups having from one to four atoms constituting a linear portion) (preferably, the above-mentioned xe2x80x9coptionally substituted aryl groupsxe2x80x9d directly combined). Particularly, such substituents are preferably electron-attracting groups. The number of such substituents may be from one to four.
Examples of the spacer include xe2x80x94(CH2)axe2x80x94 [a is an integer of from 1 to 4 (preferably an integer of from 1 to 2)], xe2x80x94(CH2)bxe2x80x94Xaxe2x80x94 [b is an integer of from 0 to 3 (preferably an integer of from 0 to 1) and Xa is an optionally substituted imino group (for example, an imino group which may be substituted with lower (C1-6) lower alkyl, lower (C3-7) cycloalkyl, formyl, lower (C2-7) lower alkanoyl, lower (C1-6) lower alkoxy-carbonyl or the like), a carbonyl group, an oxygen atom or a sulfur atom which may be oxidized (for example, xe2x80x94S(O)nxe2x80x94 (n is an integer of from 0 to 2)), xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 and xe2x80x94SO2xe2x80x94NHxe2x80x94 (preferably xe2x80x94(CH2)bxe2x80x94Xaxe2x80x94, more preferably xe2x80x94CH2xe2x80x94Oxe2x80x94). Such groups may be combined with an xe2x80x9coptionally substituted benzene ringxe2x80x9d through either of their right and left bonds, but they are preferably combined with an xe2x80x9coptionally substituted benzene ringxe2x80x9d through their right bonds.
Examples of the ring formed from R6 and R7 united together include 5- to 7-membered (preferably 5- to 6-membered) unsaturated alicyclic hydrocarbons such as C5-7 cycloalkenes (for example, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 2-cyclohexene and 3-cyclohexene), C5-6 cycloalkadienes (for example, 2,4-cyclopentadiene, 2,4-cyclohexadiene and 2,5-cyclohexadiene). The aromatic-hydrocarbon; 6-membered aromatic hydrocarbons such as benzene; 5- to 7-membered aromatic heterocyclic rings containing from one to three kinds (preferably, from one to two kinds) of at least one (preferably, from one to four, more preferably from one to two) hetero atoms selected form an oxygen atom, a sulfur atom, a nitrogen atom and the like, and unsaturated non-aromatic heterocyclic rings (aliphatic heterocyclic rings).
Examples of the xe2x80x9caromatic heterocyclic ringsxe2x80x9d as a ring which R6 and R7 are united to form include 5- to 6-membered monocyclic heterocyclic rings (for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,3-triazole, pyridine, pyridazine, pyrimidine and pyrazine). Examples of the xe2x80x9cnon-aromatic heterocyclic ringsxe2x80x9d as a ring which R6 and R7 are united to form include 5- to 6-membered non-aromatic heterocyclic rings resulting from a part of the double bonds of the above-mentioned aromatic monocyclic heterocyclic rings.
As the ring which R6 and R7 are united to form, 5- to 6-membered aromatic rings are desirable, and benzene, furan, thiophene, pyrrole, pyridine (preferably 6-membered rings) and the like are more desirable, and benzene is especially desirable.
The rings which R6 and R7 are united to form may have a substituent, examples of which include substituents such as those the xe2x80x9cbenzene ringxe2x80x9d of the above-mentioned xe2x80x9coptionally substituted benzene ringxe2x80x9d may have. From one to three, different or the same substituent may substitute at any position where the benzene ring can be substituted.
Examples of the leaving group used in this specification include halogen atoms (for example, fluorine, chlorine, bromine and iodine) and groups represented by the formula xe2x80x94O(SOm)R [in the formula, m is 1 or 2, R is an optionally substituted hydrocarbon group (preferably, optionally halogenated C1-4 alkyl, more preferably trifluoromethyl)]. Among these examples, halogen atoms are desirable, and especially, a fluorine atom and a bromine atom are desirable.
When a compound having such a substituent is a basic compound depending upon the type of the substituents mentioned above, it could be converted to a salt using an acid according to conventional methods. Such an acid may be any one that does not affect the reaction. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid and sulfamic acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, succinic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid and benzenesulfonic acid, acidic amino acids such as aspartic acid and glutamic acid, etc. can be mentioned. Moreover, when the compound obtained is a salt, it may be converted to a free base according to conventional methods.
On the other hand, when a compound having such a substituent is an acidic compound depending upon the type of the substituents mentioned above, it could be converted to a salt using a base according to conventional methods. Such a base may be any one that does not affect the reaction. For example, salts with inorganic bases, salts with organic bases and salts with basic amino acids can be mentioned. Suitable examples of the salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts and ammonium salts. Suitable examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine. Suitable examples of the salts with basic amino acids include salts with arginine, lysine and ornithine. Moreover, when the compound obtained is a salt, it may be converted to a free acid according to conventional methods.
As the xe2x80x9ccarbonic acid diesterxe2x80x9d used in this specification, compounds represented by Zxe2x80x94O(CO)Oxe2x80x94Zxe2x80x2 wherein Z and Zxe2x80x2 independently represent an optionally substituted hydrocarbon group (preferably, an optionally substituted alkyl group) can be mentioned. However, compounds which are liquid at a reaction temperature at which the reaction of the present invention is conducted. Moreover, it is desirable that Z and Zxe2x80x2 are the same. As the carbonic acid diesters, carbonic acid di-C1-4 alkyl esters such as dimethyl carbonate and diethyl carbonate are preferably used.
The reaction shown in the above-mentioned (1) is conducted under, for example, the conditions described above.
A compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof is prepared by subjecting a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof, to a ring-closing reaction.
The reaction shown in the above-mentioned (1) is preferably conducted in the presence of a base. Examples of such a base include metal hydrogen compounds (for example, hydrides of alkali metals such as sodium hydride and potassium hydride), metal hydrocarbons (for example, compounds having a chemical bond which combines C1-4 alkyl with an alkali metal directly, such as n-butyllithium), alcoholates (for example, compounds which results from substitution of the hydrogen of a hydroxyl group of a C1-4 alcohol with an alkali metal, such as NaOMe, NaOEt, t-BuONa, and t-BuOK), hydroxides of alkali metals (for example, NaOH and KOH), basic carbonates (for example, salts of alkali metals such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts), basic hydrogencarbonates (for example, hydrogencarbonates with alkali metal salts such as sodium salts and potassium salts), organic bases (for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene). Metal hydrogen compounds (for example, sodium hydride and potassium hydride) and alcoholates (for example, NaOMe, NaOEt, t-BuONa, and t-BuOK) are desirably employed, and especially, alcoholates (for example, NaOMe, NaOEt, t-BuONa, and t-BuOK) are preferably employed.
The amount of the base used in the reaction of the above-mentioned (1) is about 0.1 to 100 equivalents, preferably about 1 to 5 equivalents.
Examples of solvents preferably employed include halogen-containing solvents (for example, methylene chloride, dichloroethane and chloroform), aliphatic hydrocarbons (for example, n-hexane), aromatic hydrocarbons (for example, benzene and toluene), ethers (for example, tetrahydrofuran (THF) and diethyl ether), polar solvents (for example, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)), carbonic acid diesters (for example, di-C1-4 alkyl carbonates such as dimethyl carbonate and diethyl carbonate), formates (for example, C1-4 alkyl formate), oxalic acid diesters (for example, di-C1-4 alkyl oxalates), alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol and 2-methoxyethanol). Among them, ethers (for example, tetrahydrofuran (THF) and diethyl ether), carbonic acid diesters (for example, dimethyl carbonate and diethyl carbonate) and the like are preferably used. Although the reaction may use suitable mixed solvents, it is preferable to conduct the reaction in a solvent containing a carbonic acid diester.
The reaction temperature is usually about xe2x88x9220 to 200xc2x0 C. and preferably about 15 to 90xc2x0 C. The reaction time is usually about 0.1 to 100 hours and preferably about 1 to 50 hours.
The reaction shown in the above-mentioned (8) is conducted under, for example, the conditions described above.
A compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof is prepared by subjecting a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof, to a ring-closing reaction.
The reaction shown in the above-mentioned (8) is preferably conducted in the presence of a base. Examples of such a base include metal hydrogen compounds (for example, hydrides of alkali metals such as sodium hydride and potassium hydride), metal hydrocarbons (for example, compounds having a chemical bond which combines C1-4 alkyl with an alkali metal directly, such as n-butyllithium), alcoholates (for example, compounds which results from substitution of the hydrogen of a hydroxyl group of a C1-4 alcohol with an alkali metal, such as NaOMe, NaOEt, t-BuONa, and t-BuOK), hydroxides of alkali metals (for example, NaOH and KOH), basic carbonates (for example, salts of alkali metals such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts), basic hydrogencarbonates (for example, hydrogencarbonates with alkali metal salts such as sodium salts and potassium salts), organic bases (for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene). Metal hydrogen compounds (for example, sodium hydride and potassium hydride) and alcoholates (for example, NaOMe, NaOEt, t-BuONa, and t-BuOK) are desirably employed, and especially, alcoholates (for example, NaOMe, NaOEt, t-BuONa, and t-BuOK) are preferably employed.
The amount of the base used in the reaction of the above-mentioned (8) is about 0.1 to 100 equivalents, preferably about 1 to 5 equivalents.
Examples of solvents preferably employed include halogen-containing solvents (for example, methylene chloride, dichloroethane and chloroform), aliphatic hydrocarbons (for example, n-hexane), aromatic hydrocarbons (for example, benzene and toluene), ethers (for example, tetrahydrofuran (THF) and diethyl ether), polar solvents (for example, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)), carbonic acid diesters (for example, di-C1-4 alkyl carbonates such as dimethyl carbonate and diethyl carbonate), formates (for example, C1-4 alkyl formate), oxalic acid diesters (for example, di-C1-4 alkyl oxalates), alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol and 2-methoxyethanol). Among them, carbonic acid diesters (for example, dimethyl carbonate and diethyl carbonate) and the like are preferably used. Although the reaction may use suitable mixed solvents, it is preferable to conduct the reaction in a solvent containing a carbonic acid diester.
The reaction temperature is usually about xe2x88x9220 to 200xc2x0 C. and preferably about 15 to 90xc2x0 C. The reaction time is usually about 0.1 to 100 hours and preferably about 1 to 50 hours.
The reaction shown in the above-mentioned (15) is conducted under, for example, the conditions described above.
A compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof is prepared by causing a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof to react with a compound or a salt thereof: 
wherein each symbol is as defined above.
The reaction shown in the above-mentioned (15) is preferably conducted in the presence of a base. Examples of such a base include metal hydrogen compounds (for example, hydrides of alkali metals such as sodium hydride and potassium hydride), metal hydrocarbons (for example, compounds having a chemical bond which combines C1-4 alkyl with an alkali metal directly, such as n-butyllithium), alcoholates (for example, compounds which results from substitution of the hydrogen of a hydroxyl group of a C1-4 alcohol with an alkali metal, such as NaOMe, NaOEt, t-BuONa, and t-BuOK), hydroxides of alkali metals (for example, NaOH and KOH), basic carbonates (for example, salts of alkali metals such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts), basic hydrogencarbonates (for example, hydrogencarbonates with alkali metal salts such as sodium salts and potassium salts), organic bases (for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene). Among them, metal hydrogen compounds (for example, sodium hydride and potassium hydride) and alcoholates (for example, NaOMe, NaOEt, t-BuONa, and t-BuOK) are desirably employed, and especially, alcoholates (for example, NaOMe, NaOEt, t-BuONa, and t-BuOK), particularly mixtures of potassium carbonate-alcoholate are preferably employed.
The amount of the base used in the reaction of the above-mentioned (15) is about 0.1 to 100 equivalents, preferably about 1 to 5 equivalents.
The reaction of the above-mentioned (15) may be conducted in the presence of a catalyst. Examples of such a catalyst include catalysts containing a transition metal such as nickel and palladium.
Examples of solvents preferably employed include halogen-containing solvents (for example, methylene chloride, dichloroethane and chloroform), aliphatic hydrocarbons (for example, n-hexane), aromatic hydrocarbons (for example, benzene and toluene), ethers (for example, tetrahydrofuran (THF) and diethyl ether), polar solvents (for example, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)), carbonic acid diesters (for example, di-C1-4 alkyl carbonates such as dimethyl carbonate and diethyl carbonate), formates (for example, C1-4 alkyl formate), oxalic acid diesters (for example, di-C1-4 alkyl oxalates), alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol and 2-methoxyethanol). Although the reaction may use suitable mixed solvents, it is preferable to conduct the reaction in a mixed solvent containing a carbonic acid diester and dimethylformamide.
The reaction temperature is usually about xe2x88x9220 to 200xc2x0 C. and preferably about 15 to 90xc2x0 C. The reaction time is usually about 0.1 to 100 hours and preferably about 1 to 50 hours.
Alternatively, the reaction of the above-mentioned (15) preferably proceeds through a compound represented by the following formula: 
wherein each symbol is as defined below, or a salt thereof, as an intermediate. However, it is preferable to cause the reaction to proceed without isolation of the intermediate. When causing the reaction to proceed through the intermediate, it is also possible to cause the reaction to proceed by two steps, that is, the first step of forming the intermediate and the second step of closing the intermediate to form a ring by appropriately changing various reaction conditions (for example, the type and amount of a base, the presence or absence of a catalyst, the type of a solvent, the reaction temperature and the reaction time) wherein the first and second steps may be independent of each other and, alternatively, they also may partly overlap so that a part of the intermediates are closed to form rings during the first step. It is also possible to cause the reaction to proceed in one stage (one step) without any particular changes in reaction conditions. Furthermore, when it is necessary to form the intermediate intentionally, it is possible to form the intermediate by, for example, causing a step of forming the intermediate in the absence of an alcoholate (preferably in the presence of a basic carbonic acid salt; more preferably in the presence of potassium carbonate) and in the absence of a carbonic acid diester (preferably in the presence of a polar solvent; more preferably in the presence of dimethylformamide) to proceed, followed by causing a step of closing the intermediate to form a ring in the presence of an alcoholate (preferably in the co-presence of a basic carbonic acid salt; more preferably in the co-presence of potassium carbonate) and/or in the presence of a carbonic acid diester (preferably in the co-presence of a polar solvent; more preferably in the co-presence of dimethylformamide). Such an intermediate can be isolated, but it is preferable to conduct the reaction in a one pot without isolating the intermediate in either the case of causing the reaction to proceed in two stages or the case of causing the reaction to proceed in one stage.
On the other hand, the reaction shown in the above-mentioned (21) is conducted under, for example, the conditions described below.
A compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof is prepared by causing a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof to react with a compound or a salt thereof: 
wherein each symbol is as defined above.
The reaction shown in the above-mentioned (21) is preferably conducted in the presence of a base. Examples of such a base include metal hydrogen compounds (for example, hydrides of alkali metals such as sodium hydride and potassium hydride), metal hydrocarbons (for example, compounds having a chemical bond which combines C1-4 alkyl with an alkali metal directly, such as n-butyllithium), alcoholates (for example, compounds which results from substitution of the hydrogen of a hydroxyl group of a C1-4 alcohol with an alkali metal, such as NaOMe, NaOEt, t-BuONa, and t-BuOK), hydroxides of alkali metals (for example, NaOH and KOH), basic carbonates (for example, salts of alkali metals such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts), basic hydrogencarbonates (for example, hydrogencarbonates with alkali metal salts such as sodium salts and potassium salts), organic bases (for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene). Metal hydrogen compounds (for example, sodium hydride and potassium hydride) and alcoholates (for example, NaOMe, NaOEt, t-BuONa, and t-BuOK) are desirably employed, and especially, alcoholates (for example, NaOMe, NaOEt, t-BuONa, and t-BuOK), particularly mixtures of potassium carbonate-alcoholate are preferably employed.
The amount of the base used in the reaction of the above-mentioned (21) is about 0.1 to 100 equivalents, preferably about 1 to 5 equivalents.
The reaction of the above-mentioned (21) may be conducted in the presence of a catalyst. Examples of such a catalyst include catalysts containing a transition metal such as nickel and palladium.
Examples of solvents preferably employed include halogen-containing solvents (for example, methylene chloride, dichloroethane and chloroform), aliphatic hydrocarbons (for example, n-hexane), aromatic hydrocarbons (for example, benzene and toluene), ethers (for example, tetrahydrofuran (THF) and diethyl ether), polar solvents (for example, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)), carbonic acid diesters (for example, di-C1-4 alkyl carbonates such as dimethyl carbonate and diethyl carbonate), formates (for example, C1-4 alkyl formate), oxalic acid diesters (for example, di-C1-4 alkyl oxalates), alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol and 2-methoxyethanol). Although the reaction may use suitable mixed solvents, it is preferable to conduct the reaction in a mixed solvent containing a carbonic acid diester and dimethylformamide.
The reaction temperature is usually about xe2x88x9220 to 200 xc2x0 C. and preferably about 15 to 90xc2x0 C. The reaction time is usually about 0.1 to 100 hours and preferably about 1 to 50 hours.
Alternatively, the reaction of the above-mentioned (21) preferably proceeds through a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof, as an intermediate. However, it is preferable to conduct the ring-closing reaction without isolation of the intermediate.
The reaction shown in the above-mentioned (27) is conducted under, for example, the conditions described below.
A compound represented by the following formula: 
wherein each symbol is as defined above wherein this compound may have either an enol structure a keto structure, or a salt thereof, is prepared by subjecting a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof, to a ring-closing reaction in the presence of an alcoholate in a solvent containing a carbonic acid diester.
Examples of the alcoholate to be used in the reaction shown in the above-mentioned (27) include compounds resulting from substitution of hydrogen of hydroxyl groups of C1-4 alcohols with alkali metals, such as NaOMe, NaOEt, t-BuONa and t-BuOK.
The amount of the alcoholate to be used in the reaction shown in the above-mentioned (27) is about 0.1 to 100 equivalents, preferably about 1 to 5 equivalents.
Examples of solvents preferably employed include halogen-containing solvents (for example, methylene chloride, dichloroethane and chloroform), aliphatic hydrocarbons (for example, n-hexane), aromatic hydrocarbons (for example, benzene and toluene), ethers (for example, tetrahydrofuran (THF) and diethyl ether), polar solvents (for example, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)), carbonic acid diesters (for example, di-C1-4 alkyl carbonates such as dimethyl carbonate and diethyl carbonate), formates (for example, C1-4 alkyl formate), oxalic acid diesters (for example, di-C1-4 alkyl oxalates), alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol and 2-methoxyethanol). Among them, carbonic acid diesters (for example, dimethyl carbonate and diethyl carbonate) and the like are preferably used. Although the reaction may use suitable mixed solvents, it is preferable to conduct the reaction in a solvent containing a carbonic acid diester.
The reaction temperature is usually about xe2x88x9220 to 200xc2x00 C. and preferably about 15 to 90xc2x0 C. The reaction time is usually about 0.1 to 100 hours and preferably about 1 to 50 hours.
The reaction shown in the above-mentioned (30) is conducted under, for example, the conditions described below.
A compound represented by the following formula: 
wherein each symbol is as defined above wherein this compound may have either an enol structure a keto structure, or a salt thereof, is prepared by subjecting a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof, to a ring-closing reaction in the presence of an alcoholate in a solvent containing a carbonic acid diester.
The reaction conditions of the reaction shown in the above-mentioned (30) may be, for example, reaction conditions the same as those of the reaction shown in the above-mentioned (27).
The reaction shown in the above-mentioned (37) is conducted under, for example, the conditions described above.
A compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof is prepared by causing a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof to react with a compound or a salt thereof: 
wherein each symbol is as defined above.
The reaction shown in the above-mentioned (37) is preferably conducted in the presence of a base. Examples of such a base include metal hydrogen compounds (for example, hydrides of alkali metals such as sodium hydride and potassium hydride), metal hydrocarbons (for example, compounds having a chemical bond which combines C1-4 alkyl with an alkali metal directly, such as n-butyllithium), alcoholates (for example, compounds which results from substitution of the hydrogen of a hydroxyl group of a C1-4 alcohol with an alkali metal, such as NaOMe, NaOEt, t-BuONa, and t-BuOK), hydroxides of alkali metals (for example, NaOH and KOH), basic carbonates (for example, salts of alkali metals such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts), basic hydrogencarbonates (for example, hydrogencarbonates with alkali metal salts such as sodium salts and potassium salts), organic bases (for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene). Among them, basic carbonic acid salts (for example, carbonic acid salts of alkali metal salts sodium salts and potassium salts or alkaline earth metal salts such as calcium salts and magnesium salts) and the like, particularly potassium carbonate is preferably used.
The amount of the base used in the reaction of the above-mentioned (37) is about 0.1 to 100 equivalents, preferably about 1 to 5 equivalents.
The reaction of the above-mentioned (37) may be conducted in the presence of a catalyst. Examples of such a catalyst include catalysts containing a transition metal such as nickel and palladium.
Examples of solvents preferably employed include halogen-containing solvents (for example, methylene chloride, dichloroethane and chloroform), aliphatic hydrocarbons (for example, n-hexane), aromatic hydrocarbons (for example, benzene and toluene), ethers (for example, tetrahydrofuran (THF) and diethyl ether), polar solvents (for example, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)), carbonic acid diesters (for example, di-C1-4 alkyl carbonates such as dimethyl carbonate and diethyl carbonate), formates (for example, C1-4 alkyl formate), oxalic acid diesters (for example, di-C1-4 alkyl oxalates), alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol and 2-methoxyethanol). The reaction may use suitable mixed solvents, and particularly, dimethylformamide is preferably used.
The reaction temperature is usually about xe2x88x9220 to 200xc2x0 C. and preferably about 15 to 90xc2x0 C. The reaction time is usually about 0.1 to 100 hours and preferably about 1 to 50 hours.
The compound represented by the following formula: 
wherein R1 is an electron-attracting group; R2, R3, R4 and R5 are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; ring A is an optionally substituted benzene ring; and R8 is a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof, wherein the compound or a salt thereof is obtained in the reaction shown in the above-mentioned (37), is a novel compound which has not been disclosed in any literature.
In the aforementioned formula, an optionally esterified carboxyl group is desirable as R1, a hydrogen atom is desirable as R8, and a hydrogen atom is desirable as R2, R3, R4 and R5.
Among the raw compounds to be used in the reaction shown in the above-mentioned (37), a compound represented by the following formula: 
wherein Xxe2x80x2 represents a halogen atom, R8 represents a hydrogen atom or an optionally substituted hydrocarbon group, Y represents a bond or a spacer, Rxe2x80x2 represents a C1-4 alkoxy which may be substituted with a substituent selected from halogen atoms and C1-4 alkoxy, or a salt thereof, is a novel compound which has not been disclosed in any literature.
Examples of the halogen atom represented by Xxe2x80x2 include fluorine, chlorine, bromine and iodine. Among the, fluorine is preferable. A hydrogen atom is preferably used as R8.
Examples of the xe2x80x9cspacerxe2x80x9d represented by Y include divalent groups wherein the number of the atoms constituting their linear portion is from one to four, such as xe2x80x94(CH2)axe2x80x94 [a represents an integer of from 1 to 4, preferably an integer of from 1 to 2], xe2x80x94(CH2)bxe2x80x94Xaxe2x80x94 [b represents an integer of from 0 to 3, preferably an integer of from 0 to 1, and Xa represents an optionally substituted imino group (for example, an imino group which may be substituted with a lower (C1-6) lower alkyl, a lower (C3-7) cycloalkyl, formyl, a lower (C2-7) lower alkanoyl, a lower (C1-6) lower alkoxy-carbonyl or the like), a carbonyl group, an oxygen atom or a sulfur atom which may be oxidized (for example, xe2x80x94S(O)nxe2x80x94 wherein n represents an integer of from 0 to 2)], xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 and xe2x80x94SO2xe2x80x94NHxe2x80x94. Preferred is xe2x80x94(CH2)bxe2x80x94Xaxe2x80x94 and more preferred is xe2x80x94CH2xe2x80x94Oxe2x80x94. These divalent groups may be combined with a xe2x80x9cbenzene ring having a substituent Xxe2x80x2xe2x80x9d using either their right bonds or their left bond, but it is preferable to be combined with the xe2x80x9cbenzene ring having a substituent Xxe2x80x2xe2x80x9d through their right bonds. A bond or xe2x80x94CH2xe2x80x94Oxe2x80x94 is preferably used as Y. A bond is more preferably used.
Rxe2x80x2 may substitute at any position and preferably substitutes at the para position. As Rxe2x80x2, ethoxy or propoxy is preferably employed.
A compound represented by the above-shown formula: 
wherein each symbol is as defined above, or a salt thereof can be prepared by, for example, reaction (i), (ii) or methods according to them.
Reaction (i)
A compound represented by the following formula: 
wherein each symbol is as defined below, or a salt thereof can be prepared by subjecting a compound represented by the following formula: 
wherein Xxe2x80x3 represents a leaving group and each of the other symbol is as defined above, or a salt thereof, to substituted-phenylation using a compound represented by the following formula: 
wherein M represents MgX, B(OH)2, B(OR)2 or SnR3, X, R and Rxe2x80x2 are as defined above, or a salt thereof.
In one of the above formulas, examples of the leaving group represented by Xxe2x80x3 include halogen atoms (for example, fluorine, chlorine, bromine and iodine), groups represented by a formula xe2x80x94O(SOm)R [in the formula, m represents 1 or 2, and R represents an optionally substituted hydrocarbon group (preferably C1-4 alkyl which may be halogenated, and more preferably trifluoromethyl)]. Among them, preferred are halogen atoms. Particularly, iodine, bromine and the like are preferred.
This reaction may be conducted in the presence of a catalyst. Examples of such a catalyst include catalysts containing a transition metal such as nickel and palladium.
Dimethoxyethane, acetone, aromatic hydrocarbons (for example, benzene and toluene), ethers (for example, tetrahydrofuran (THF), diethyl ether and dioxane) and the like are used as a reaction solvent, but the reaction may use suitable mixed solvents. Moreover, water, alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol and 2-methoxyethanol) or the like may appropriately coexist.
The reaction temperature is usually about xe2x88x9210 to 200xc2x0 C. and preferably about 20 to 100xc2x0 C. The reaction time is usually about 0.1 to 50 hours and preferably about 1 to 20 hours.
Reaction (ii)
A compound represented by the following formula: 
wherein each symbol is as defined below, or a salt thereof can be prepared by causing a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof, to react with a compound represented by the following formula: 
wherein Xxe2x80x2xe2x80x3 represents a leaving group, and b and Rxe2x80x2 are as defined above, or a salt thereof.
In one of the above formulas, examples of the leaving group represented by Xxe2x80x2xe2x80x3 include halogen atoms (for example, fluorine, chlorine, bromine and iodine), groups represented by a formula xe2x80x94O(SOm)R [in the formula, m represents 1 or 2, and R represents an optionally substituted hydrocarbon group (preferably C1-4 alkyl which may be halogenated, and more preferably trifluoromethyl)]. Among them, preferred are halogen atoms. Particularly, iodine, bromine, chlorine and the like are preferred.
This reaction is preferably conducted in the presence of a base. Examples of such a base include metal hydrogen compounds (for example, hydrides of alkali metals such as sodium hydride and potassium hydride), metal hydrocarbons (for example, compounds having a chemical bond which combines C1-4 alkyl with an alkali metal directly, such as n-butyllithium), alcoholates (for example, compounds which results from substitution of the hydrogen of a hydroxyl group of a C1-4 alcohol with an alkali metal, such as NaOMe, NaOEt, t-BuONa, and t-BuOK), hydroxides of alkali metals (for example, NaOH and KOH), basic carbonates (for example, salts of alkali metals such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts), basic hydrogencarbonates (for example, hydrogencarbonates with alkali metal salts such as sodium salts and potassium salts), organic bases (for example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene).
The amount of the base used in this reaction is about 0.1 to 100 equivalents, preferably about 1 to 5 equivalents.
Examples of solvents preferably employed include halogen-containing solvents (for example, methylene chloride, dichloroethane and chloroform), aliphatic hydrocarbons (for example, n-hexane), aromatic hydrocarbons (for example, benzene and toluene), ethers (for example, tetrahydrofuran (THF) and diethyl ether), polar solvents (for example, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)), carbonic acid diesters (for example, di-C1-4 alkyl carbonates such as dimethyl carbonate and diethyl carbonate), formates (for example, C1-4 alkyl formate), oxalic acid diesters (for example, di-C1-4 alkyl oxalates), alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol and 2-methoxyethanol). The reaction may use suitable mixed solvents.
The reaction temperature is usually about xe2x88x9220 to 200xc2x0 C. and preferably about 15 to 90xc2x0 C. The reaction time is usually about 0.1 to 100 hours and preferably about 1 to 50 hours.
The compounds or their salts to be obtained by the reactions shown in the above-mentioned (1), (8), (15), (21), (27) and (30) themselves are useful as intermediates for synthesizing anilide derivatives disclosed in WO99/32100, WO99/32468, PCT/JP99/07148 and the like by condensing aniline derivative therewith in known methods.
For example, when a compound represented by the following formula: 
wherein R1xe2x80x2 represents an esterified carboxyl group and each of the other symbols is as defined above, or a salt thereof, preferably a compound represented by the following formula: 
wherein each symbol is as defined above, or a salt thereof, is used as a raw material, a compound represented by the following formula: 
wherein each symbol is as defined above or below, or a salt thereof, preferably a compound represented by the following formula: 
wherein each symbol is as defined above or below, or a salt thereof, can be prepared by subjecting, as demanded, the raw material to, for example, a reaction of converting an esterified carboxyl group as R1xe2x80x2 to a carboxyl group and a reaction of oxidizing the sulfur atom in the thiepine ring according to known reactions (for example, a hydrolysis reaction of an ester and an oxidation reaction of a sulfur atom), followed by subjecting the resulting compound represented by the following formula: 
wherein each symbol is as defined above, a salt thereof or a reactive derivative thereof, preferably a compound represented by the following formula: 
wherein each symbol is as defined above, a salt thereof or a reactive derivative thereof, to a condensation reaction with a compound represented by the following formula: 
wherein Ra and Rb, respectively, represent an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or a salt thereof (for example, known condensation reactions disclosed in WO99/32100 and WO99/32468).
In the above formulas, examples of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by Ra and Rb include those the same as the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R2, R3, R4, R5, R6 and R7.
In the above formulas, as Ra, optionally substituted linear hydrocarbon groups (for example, optionally substituted alkyls and optionally substituted alkenyls) are preferable, optionally substituted lower C1-6 alkyl groups are more preferable, and a methyl group is particularly preferable.
As Rb, optionally substituted alicyclic hydrocarbon groups (non-aromatic cyclic hydrocarbon groups) (for example, optionally substituted cycloalkyls and optionally substituted cycloalkenyls; preferably, optionally substituted lower C3-8 cycloalkyl groups; more preferably, cyclohexyl) or optionally substituted alicyclic heterocyclic groups (non-aromatic heterocyclic groups) (preferably, optionally substituted saturated alicyclic heterocyclic groups (preferably 6-membered cyclic groups); more preferably, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrothiopyranyl or optionally substituted piperidyl; particularly preferably, tetrahydropyranyl) are preferable.
The above-mentioned condensation reaction is conducted by the conventional peptide synthesis approach. The peptide synthesis approach can be conducted according to any known method, for example, the methods disclosed in M. Bodansky and M. A. Ondetti, xe2x80x9cPeptide Synthesisxe2x80x9d, Interscience, New York, 1966; M. M. Finn and K. Hofmann, xe2x80x9cThe Proteinsxe2x80x9d, Vol. 2, Edited by H. Nenrath and R. L. Hill, Academic Press Inc., New York, 1976; and Nobuo IZUMIYA, xe2x80x9cFundamentals and Experiments of Peptide Synthesisxe2x80x9d, Maruzen Co., Ltd., 1985, for example, an azide method, a chloride method, an acid anhydride method, a mixed acid anhydride method, a DCC method, an active ester method, a method using a Woodward reagent K, a carbonyldiimidazole method, an oxidation-reduction method, a DCC/HONB method, a WSC method and a method using diethyl cyanophosphate. This condensation reaction can be conducted in a solvent. Examples of such a solvent include anhydrous or hydrous N,N-dimethylformamide (DMF), dimethyl sulfoxide, pyridine, chloroform, dichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile and appropriate mixtures of some of these solvents.
This condensation reaction usually uses about one to two moles of an amine compound per one mole of a carboxylic acid derivative. The reaction temperature is usually from about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably from about xe2x88x9210xc2x0 C. to about 30xc2x0 C. The reaction time is from about one to about 100 hours, preferably from about 2 to about 40 hours. The anilide derivative thus obtained is can be isolated and purified by known separation purification means, such as concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
The present invention will be described in more detail below with reference to Referential Examples and Examples. However, these are mere examples and never limit the present invention.